Exome sequencing uncovers promising candidate genes for foetal structural malformations

Area of Science:

• Medical Genetics
• Fetal Medicine
• Genomics

Background:

• Prenatal ultrasonography detects fetal structural anomalies in up to 5% of pregnancies, often with suspected genetic causes.
• Conventional genetic tests (karyotyping, FISH, CMA) and whole-exome sequencing (WES) have a limited combined diagnostic yield of 40% in malformed fetuses.
• Most cases of fetal malformations remain undiagnosed, highlighting the need for novel genetic factor identification.

Purpose of the Study:

• To identify novel genetic factors associated with severe fetal structural malformations.
• To evaluate the diagnostic yield of comprehensive genetic analysis in a low-resource setting.
• To establish genotype-phenotype correlations for undiagnosed fetal anomalies.

Main Methods:

• Comprehensive genetic analysis of 44 medically terminated fetuses with severe structural malformations.
• Utilized karyotyping, fluorescent in situ hybridization (FISH), chromosomal microarray (CMA), and whole-exome sequencing (WES).
• Reanalyzed WES data using an in-house pipeline and Exomiser for inconclusive cases.

Main Results:

• Identified genetic anomalies in 18.1% of cases, including trisomies 21, 13, and XXY mosaicism.
• Chromosomal microarray (CMA) detected copy number variations (CNVs) in 13.6% of cases, with five pathogenic CNVs.
• Whole-exome sequencing (WES) increased the diagnostic yield by 4.5% and identified six candidate genes (RUNX2, PALLD, KMT2D, FBN2, CPLANE1, KMD1A) linked to specific malformations.

Conclusions:

• This study provides insights into the genetic evaluation of malformed fetuses in low-resource settings.
• Identified candidate genes offer potential for functional studies to establish genotype-phenotype correlations.
• The comprehensive genetic approach enhances diagnostic yield for fetal structural anomalies.